Lower alkoxytetrahydropyranyl ethers of anabolic steroids



United States Patent 3,520,880 LOWER ALKOXYTETRAHYDROPYRANYL ETHERS OF ANABOLIC STEROIDS Alexander D. Cross, Mexico City, Mexico, and John A.

Edwards, Los Altos, Calif., assignors to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed May 22, 1968, Ser. 'No. 731,300

' Int. Cl. C07c 173/00 US. Cl. 260-23955 36 Claims ABSTRACT OF THE DISCLOSURE The 4 (lower)alkoxytetrahydropyran 4' yl ethers of anabolic steroids have high oral activities.

This invention relates to novel and useful 4' (lower) alkoxytetrahydropyran 4 yl ethers of anabolic steroids, the steroid nucleus thus bearing a new group represented by the formula:

wherein -OR is a (lower) primary or secondary alkoxy group. In the preferred embodiment, this new group is added at the C-3, C-17p or C-3,17;9 positions of the steroid nucleus.

The preferred anabolic steroidal ethers of this invention have the formulas:

R13 R10 F O- O= --R 1 1 I Ru Ru (I) (II) X Y 11 --R1z "-R12 q R23 R13 l I Rz'r' Rico 0: I

X4 X4 17 --R1z "R12 Rap i i 3 /i 4 Rm;

R2 V VI wherein R10, R11, R13, R15, R22, and R23 each is hydrogen or methyl (preferably one of R and R is methyl);

R is hydrogen or lower alkyl;

R is hydrogen or chloro;

R is lower alkyl or lower cycloalkyl;

R is methyl or ethyl;

R R and R each is hydrogen, methyl, fluoro, or

chloro; and R is not present when Z, is a double bond;

X is 4' (lower)alkoxytetrahydropyran 4 yloxy;

X is keto or tat-hydrogen together with ,B-X, fl-hydrogen, or fi-hydroxy, and conventional hydrolyzable esters thereof;

X is X, hydroxy, or conventional hydrolyzable esters thereof; and at least one of X and X is X; and

Z and Z each is a single bond or double bond.

The term anabolic steroids is used herein to denote androstanes and 19 norandrostanes having anabolic activity. The preferred anabolic steroids have 4 (lower)- alkoxytetrahydropyran 4 yloxy groups at positions C-3/3, Cl7,6, or C3B,17fl of the steroid nucleus.

The compounds represented by Formulas I-VI are anabolic agents with a favorable anaboliczandrogenic ratio, also possess anti-estragenic, anti-gonadotrophic, and anti-fibrillatory activities, and can be used in the same manner as testosterone. These compounds are administered by the usual routes, whether orally or parenterally, either alone or in conjunction with other medicinal agents, or in pharmaceutically acceptable, non-toxic compositions formed by the incorporation of any of the normally employed excipients.

The terms (lower)alkyl and derivations thereof appearing in the above definitions and elsewhere in the instant specification denote alkyl groups containing from one to six carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl, and the like.

The term conventional hydrolyzable ester as used herein denotes those hydrolyzable ester groups conventionally employed in the steroid art, preferably those derived from hydrocarbon carboxylic acids or phosphoric acids and their salts. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from one to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the Scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecanoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi 5,13 dimethylglutarate, acetoxyacetate, 2 chloro 4 nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, [3 chloropropionate, trichloroacetate, fl chlorobutyrate, dihydrogen phosphate, dibenzyl phosphate, benzyl hydrogen phosphate, sodium benzyl phosphate, cyclohexylammoniurn benzyl phosphate, sodium phenyl phosphate, sodium ethyl phosphate, di p nitrobenzyl phosphate, sodium o-methoxyphenyl phosphate, cyclohexylammonium p cyanobenzyl phosphate, sodium phenacyl phosphate, benzyl o carbomethoxyphenyl phosphate, and the like.

By the term aryl are included aryl, aralkyl, and alkaryl groups, such as phenyl, p chlorophenyl, p methoxyphenyl, benzyl, phenethyl, tolyl, ethylphenyl, and the like. The wavy line (5) designates and includes both the alpha and beta configurations.

The novel 17p (4 loweralkoxytetrahydropyran 4- yloxy) ethers of Formulas I, II, III, and IV can be prepared from the corresponding 175 hydroxy compounds by a process which can be illustrated schematically as follows:

In these formulas, 10, 11, 12, 13, 14, 15, 16, 17 R R and X have the meanings given above with respect to Formulas I-IV.

In carrying out the above illustrated process, the 17phydroxy compounds (I, II, III, and IV) are reacted under substantially anhydrous conditions with an excess of 4-(lower)alkoxy-5',6-dihydro-2H-pyran; for example, with from about two to about 50 or more molecular equivalents for each hydroxyl group in the steroid starting material, in the presence of a small amount of an acidic catalyst, such as hydrochloric acid, p-toluenesulfonic acid, boron trifiuoride etherate, and the like, either alone or together with an inert, organic solvent, such as benzene, diethyl ether, methylene chloride, or the like, at a temperature ranging from about C. to about 80 C. (preferably at around room temperature, i.e., C.) for about five minutes to about 48 hours, thus giving the corresponding 17/3 (4 loweralkoxytetrahydropyran 4'- yloxy) ethers represented by Formulas I-IV.

The 3, 176-, and 3,17,8-bis(4-loweralkoxyetrahydropyran-4-yloxy) ethers represented by Formulas V and VI can be prepared from the corresponding androst-4-cn- 17fl-ol-3-one and 19-norandrost-4-cnfi-Ql-3-Q11e 60 pounds by a process which can be illustrated schematically as follows:

OH X Rnku Ri7| R13 R13 Pl o l X Z4 Z4 /R20 R2 Rm (XVII) Rio (XIV) l X OJRzl RnL R13l Rap Bra Z4 Z4 /R20 2 R19 (XVIII) R1 (XXI) l X 0 R21 -'-Ru R17 R12 Riafi Ria HO 1 w X Z4 Z4 /R2o Rn (XIX) Rio (XXII) X OH -Ria 1| --R12 Ria R1:

l? R21CO X Z4 Z4 R R20 20 (XX) R" (XXIII) In these formulas, R R R R R X, and Z have the meanings given with respect to Formulas V and VI above, and R is an alkyl, alkenyl, cycloalkenyl, or cycloalkyl group having up to 12 carbon atoms.

In carrying out the above-illustrated process, methylandrost-4-en-17B-ol-3-one, for example, (XVII: R and R =hydrogen; R R and R =methyl) is reacted under substantially anhydrous conditions with an excess of 4-(lower)alkoxy-5, '-dihydro-2H-pyran as described above with respect to Formulas I-IV to give the corresponding 17a-methyl-17fi-(4-loweralkoxytetrahydropyran-4'-yloxy)-androst-4-en-3-one (XVIII). This compound can be converted to the 3p-hydroxy derivative by dissolving it in an inert solvent such as a (lower)alkanol, such as methanol, an ether, such as dioxone or tetrahydrofurane or the like, and reacting it under neutral conditions with a metal hydride, such as lithium tri-t-butoxy aluminum hydride, at temperatures ranging from room.

temperature to reflux temperature for from about one hour to about 24 hours, thus giving the corresponding 17a-methy1 17/3 (4-loweralkoxytetrahydropyran-4'- yloxy)androst-4-en-3fi-ol (XIX). To obtain the 3/i-ester of Formula XX, the product can be reacted with an organic acid anhydride in pyridine or with a solution of ethylmagnesium bromide and the desired organic chloride in anhydrous ether; for example, reaction with acetic anhydride yields 3fi-acetoxy-l7zx methyl-17fl-(4'-loweralkoxytetrahydropyran 4' yloxy)androst-4-ene (XX: R methyl). By this procedure, the compounds represented by Formulas XVIII-XX are obtained with other androst- 4-en-17/3-ol-3-ones wherein R is hydrogen or lower alkyl; R is hydrogen or methyl; R is ethyl or methyl; and R and R each is hydrogen, methyl, fiuoro, or chloro.

In carrying out the above-illustrated process to form the 3,8(4-loweralkoxytetrahydropyran-4-yloxy) ethers of Formulas XXII and XXIII from the compounds represented by Formula XVII, the keto group at C-3 is first reduced to 3fl-hydroxy such as by reaction with lithium tri-t-butoxy aluminum hydride as described above with respect to Formula XIX to yield, for example, 17a-methylandrost-4-ene-3B,17,8-diol. The product is then esterified with one molar equivalent of acetic anhydride by procedures described with respect to Formula XX to form a mixture of mono-esters. The 17B-acetoxy compounds are separated from the mixture by conventional chromatographic techniques. For example, l7u-methylandrost-4- en-17fl-ol-3-one (XVII: R R and R =methy1; R and R =hydrogen) is reduced to I7OC-Il'ICIhYIfiHdIOSt-4- ene-3fl,17[i-diol and the product is esterified to form 1704- methyl-17B-acetoxyandrost-4-en-3B-ol (XXI). This compound is then reacted with 4-(lower)alkoxy-5,6-dihydro-2H-pyran as described above with respect to Formula XVIII to yield the corresponding 3B-ether, for example, 3,8 (4' loweralkoxytetrahydropyran 4 -yloxy) 17cc methyl 17p acetoxyandrost 4 ene (XXII). If the 17fl-hydroxy compound as described in Formula XXIII is desired, the latter product is hydrolyzed by conventional procedures, for example, in a solution of potassium hydroxide in methanol, to yield the desired product, for example, 3p-(4-loweralkoxytetrahydropyran- 4-yloxy)-l7a-methylandrost-4-en-1713-01. By this procedure, other 3B-(4'-loweralkoxytetrahydropyran-4'-yloxy) compounds represented by Formulas XXII and XXIII can be prepared from the corresponding compounds of Formula XVII wherein R is hydrogen or lower alkyl; R is hydrogen or methyl; R is methyl or ethyl; and R and R each is hydrogen, methyl, fluoro, or chloro.

In the above-illustrated processes to make the 36,175- bis(4'-loWeralkoxytetrahydropyran-4'-yloxy) ethers represented by Formula XXIV, the corresponding 17fi-hydroxy-3-keto of Formula XVII is first reduced by reaction with a metal hydride, such as lithium tri-t-butoxy aluminum hydride, to yield the corresponding 3,8-hydroxy compound as described above with respect to the compounds of Formula XIX. The 3,6,17B-dihydroxy compound, for example, 17a-methylandrost-4-ene-3fi,17B-diol, is then reacted With a molar excess of 4-(1ower)alkoxy-5,6'-dihydrO-ZH-pyran as described above With respect to Formula XVIII to yield the corresponding 3B,17p-bis(4'-1oweralkoxytetrahydropyran-4'-yloxy) ether, such as, for example, 3,5,17B-bis(4-methoxytetrahydropyran-4'-yloxy)- 17a-methylandrost-4-ene. By this procedure, other compounds represented by Formula XXIV, wherein R R R R R and X are as defined above, can be obtained from the corresponding substituted compounds represented by Formula XVII.

By the above-illustrated procedures, the 35-, 1713-, and 3,173 bis(4 loweralkoxytetrahydropyran 4' yloxy)- 19 norandrosta 4,9() dienes represented by Formula VI can be prepared from the corresponding 19-norandrosta-4,9(10)-dien-17[i-ol-3-ones.

The 4-(lower) alkoxy-S,6'-dihydro-2H-pyran reactants used to form the ethers of this invention can be prepared by Well-known methods. For example, tetrahydro-4-pyrone can be reacted with a primary or secondary lower alkanol under acidic conditions to form the intermediate, 4,4'-di(lower)alkoxytetrahydropyran, which upon distillation with an acid, such as toluenesulfonic acid or mesitylenesulfonic acid, yields the 4-(lower)alkoxy 5',6 dihydro-ZH-pyran product. Such a method is described by Reese et al., I. Am. Chem. Soc. 89, 3367 (1967). The lower alkanol is preferably methanol but it can be other lower alcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, amyl alcohol, hexanol, and and the like, to form the corresponding pyrans, such as, for example, 4-methoxy-5',6'-dihydro-2H-pyran, 4-ethoxy-S,6-dihydro-2H-pyran, etc.

The ethers of Formula I are prepared from known 19- norandrostan-17-ol-3-ones and androstan-l7-ol-3-ones containing the substituents represented by R R R and R See, for example, JACS, 81, 428 (1959); IACS, 76, 5024 (1954); and U.S. Pats. 2,756,244 and 2,844,602.

In preparing the ethers of Formula II, the substituents R R R and R are likewise present in the known starting steroids. See, for example, Lo Sperimentale 106, 490 (1956); J. Org. Chem. 21, 1432 (1956); JACS, 80, 4717 (1958); Lo Sperimentale 104, 490 (1956); Tetrahedron 3, 14 (1958); JACS, 75, 5366 (1953); and U.S. Pats. 3,028,401 and 3,213,986.

In preparing the ethers of Formula III, the substituents R R R and R are also present in the known starting steroids. See, for example, U.S. Pat. 3,067,214.

In preparing the ethers of Formula IV, the substituents R R and R are present in the known starting compounds and can be obtained from known compounds by conventional techniques. See, for example, Int. Steroid Congress, Milan, p. 68 (1962); JACS, 82, 5494 (1960); German Pat. No. 1,096,356; and U.S. Pat. No. 3,361,774.

In preparing the ethers of Formula V, the substituents R R R 7, R and R are present in the known starting compounds. See, for example, IACS, 80, 4717 (1958); JACS, 83, 4663 (1961); J. Pharm. Pharmacol 9, 929 (1957); Ber., 71, 1024 (1938); Endocrinology, 65, 265, and U.S. Pats. 3,028,401, 3,047,592, 3,052,693, and 3,067,214.

In preparing the ethers of Formula VI, the substituents R and R are also present in the known starting compounds. See, for example, JACS, 83, 4463 (1961); J. Chem. Soc., 4472 (1964); and U.S. Pats. 3,086,027, 3,248,294, 3,250,793, and 3,257,278.

Starting materials having an 18-methyl group (R ethyl) are obtainable by methods described by Smith et al. in Experimentia, vol. 19, pp. 394396 (1963).

In reacting the C-3, C17,8, and C3,17/3 hydroxy compounds herein-disclosed with 4-(lower)alkoxy-5',6-dihydro-2H-pyran by the procedures described herein to form the 4-(lower) alkoxytetrahydropyran-4'-yl ethers of this invention, a second series of ethers, that is, 5,6'- dihydro-2H-pyran-4-yl ethers of the starting materials are formed. This second series of ethers correspond to those represented by Formulas I, II, III, IV, V, and VI wherein X is the 5',6-dihydro-2H-pyran-4-yloxy group. Hydrocarbon solvents for the reaction medium, higher catalyst concentrations, and longer reaction times increase the yield of the 5',6-dihydro-2H-pyran-4'-yloxy compounds; use of ether or tetrahydrofuran solvents, lower catalyst concentrations, and shorter reaction times increase the yield of the 4'-(lower)a1koxytetrahydropyran-4-yloxy compounds. This second series of compounds can be separated from the reaction products by conventional chromatographic techniques.

These 5,6'-dihydro-2H-pyran-4'-yl ethers are anabolic agents with a favorable anaboliczandrogenic ratio, also possess anti-estrogenic, anti-gonadotrophic, and anti-fibrillatory activities, and can be used in the same manner as testosterone. These compounds are administered by the usual routes, whether orally or parenterally, either alone or in conjunction with other medicinal agents, or

in pharmaceutically acceptable, non-toxic compositions formed by the incorporation of any of the normally employed excipients.

Examples of ethers are 2a-methyl-l7p- (,6-dihydro-2H-pyran-4'-yloxy) -5aandrostan-3one,

4a-methyl-17 8-(5',6'-dihydro-2H-pyran-4'-yloxy) -50L- androstan-S-one,

17/3- (5',6'-dihydro2H-pyran-4'-yloxy)androst-4-en-3- one,

17p-(5,6'-dihydro-2H-pyran-4'-yloxy) -l9-norandrost- 4-en-3-one,

4-chloro-l 7,3- (5',6'-dihydro-2H-pyran-4-yloxy) -19-norandrost-4-en-3-one,

7 a-methyl-17 13-(5 ,6-dihydro-2H-pyran-4-yloxy) -19- norandrost-4-en-3-one,

3-cyclopentoxy-17ia-methyl-17fl-'(5',6'-dihydro-2H- pyran-4-yloxy l9-norandrosta-3 ,5 -diene,

3-cyclopentoxy-17a,l8-dimethyll7fl-(5',6-dihydro-2H- pyr-an-4'-yloxy) -19-norandrosta-3,5-diene,

3-methoxy-l7a, 1 8-dimethyl-17 ,3- (5',6'-dihydro-2H-pyran- 4'-yloxy-3 19-norandrosta-3,S-diene,

2,17u-dimethyl-17B-(5',6'-dihydro-2H-pyran-4-yloxy)- 5a-androst-1-en-3-one,

17a-methyl-l7/3-(5',6-dihydro-2H-pyran-4'-yloxy)-19- norandrost-4-en-3-one,

3fi-acetoxy-17a-methyl-17/3-(5',6"-dihydro-2H-pyran-4'- yloxy) l 9-norandrost-4-ene,

17a,18-dimethyl-l7B- (5',6"-dihydro-2H-pyran-4'-yloxy)- 19-norandrost-4-en-3-one,

3-acetoxy- 17a, 1 S-dimethyl- 17,8- (5',6'-dihydro-2H-pyran- 4'-yloxy) l9-norandrost-4-ene,

6oz, l7u-dimethyl-17fi-(5',6'-dihydro-2H-pyran-4'-yloxy) 19-norandrosta-4,6-dien-3-one,

6a,18-dimethyl-17ot-ethyl-17fi-(5',6'-dihydro-2H-pyran- 4'-yloxy) -19-norandrosta-4,6-dien-3-one,

3- (5,6-dihydro-2H-pyran-4'-yloxy)-17oc-Inethyl-17- acetoxy-19-norandrost-4-ene,

3,17f3-bis(5',6'-dihydr0-2H-pyran-4'-yloxy)-l7a-methyl- 19-norandrost-4-ene,

l7B-(5',6'-dihydro-2H-pyran-4-yloxy)-19-norandrosta- 4,9 ,1 l-trien-S-one,

17 a-methyl-175- 5 ',6'-dihydro-2H-pyran-4-yloxy-l9- norandrosta-4,9( 10),11-trien-3-one,

3fl-(5',6'-dihydro-2H-pyran-4'-yloxy) -17u-methyl-l9- norandorsta-4,9(10),l1-trien-17fl-ol, and the like.

This invention is further illustrated by the following specific but non-limiting examples.

suitable 5',6'-dihydro-2H-pyran-4-yl EXAMPLE 1 To a solution of 1 g. of 5a,19-norandrost-l7fl-ol-3-one and 25 cc. of benzene there is added 2 cc. of 4'-methoxy- 5,6'-dihydro-2H-pyran. Next, approximately 5 cc. of the mixture of benzene and dihydropyran is distilled off to remove moisture, and the remaining mixture is then cooled to room temperature. To the cooled mixture is then added 0.1 g. of p-toluenesulfonic acid, and the resulting reaction mixture is held at room temperature for 72 hours. Following this reaction period, the reaction mixture is washed with an aqueous 5% sodium carbonate solution and then with water until a neutral pH is obtained, then dried over anhydrous sodium sulfate and evaporated to dryness. The dry residue is then chromatographed by passing it, dissolved in hexane, through a column of neutral alumina, thus giving 17,8-(4'-methoxytetrahydropyran- 4'-yloxy)-5ot,19-norandrost-3-one.

By repeating this procedure in every detail but one, namely, replacing the 4'-methoxy-5,6'-dihydro-2H-pyran with 4'-propoxy-5',6-dihydro-2H-pyran, 4'-isopropoxy- 5,6'-dihydro-2H-pyran, 4'-butoxy-5',6-dihydro-2H-pyran, 4'-isobutoxy-5,6'-dihydro-2H-pyran, 4'-amyloxy-5, 6'-dihydro-2H-pyran, and 4-hexoxy-5',6'-dihydro-2H-pyranthe corresponding 17B-(4'-ethoxytetrahydropyran- 4'-yloxy)-5a,19-norandrost-3-one, 17/3-(4-propoxytetrahydropyran-4'-yloxy)-5u,19-norandrost-3-one, (4'-isopropoxytetrahydropyran-4-yloxy)-5a,19-norandrost 3 one, 17fi-(4'-butoxytetrahydropyran 4' yloxy)-5a,l9 norandrost-3-one, 17/3-(4' isobutoxytetrahydropyran-4- yloxy)-5a,19-norandrost-3-one, 17 3-(4'-amyloxytetrahydropyran-4'-yloxy)-5a,19-norandrost-3-one, and 1713-(4'- hexoxytetrahydropyran-4'-yloxy)-5a,19-norandrost-3 one are obtained.

EXAMPLE 2 By repeating the procedure of Example 1 in every detail but one, namely, replacing the 5a,19-norandrost-17fiol-3-one with Za-methyI-Sa,19-norandrost-17p-ol-3-one, 2a-methyl-5a-androst-17fl-ol-3-one, 4oz methyl-5a,19-norandrost-l7B-ol-3-one, 2 x,17a dimethyl-5a,l9-norandrost- 17;9ol-3-one, 4a methyl 17a ethyl-5a-androst-l7fiol-3-one, and 4a methyl-5a-androst-175-ol-3-onethe corresponding 20: methyl-17B-(4'-methoxytetrahydropyran-4'-yloxy)-5a,19-norandrost-3-one, 2oz methyl 1713- (4' methoxytetrahydropyran 4 yloxy) -5a androst-3- one, 40: methyl 17B (4'-methoxytetrahydropyran-4- yloxy)-5a,19-norandrost-3-one, 2a,17a dimethyl 17,8- (4' methoxytetrahydropyran 4' yloxy)-5a,19-norandrost-3-one, 4a methyl-17a ethyl-17B-(4'-methoxytetrahydropyran-4-yloxy)-5a-androst 3 one, and 40amethyl 17B (4 methoxytetrahydropyran 4-yloxy)- 5a-androst-3-one ethers are obtained.

By repeating this procedure with the other dihydropyrans of Example 1, that is, 4'-ethoxy-5',6'-dihydro-2H- pyran, 4'-propoxy-5',6'-dihydro-2H-pyran, 4 butoxy-S', 6-di.hydr0 2H pyran, 4'-isobutoxy-5,6-dihydro 2H- pyran, 4-amyloxy-5,6'-dihydro-2H-pyran, and 4'-hexoxy 5,6' dihydro 2H-pyranthe corresponding 4- ethoxytetrahydropyran-4'-yloxy, 4' propoxytetrahydropyran-4'-yloxy, 4' isopropoxytetrahydropyran-4'-yloxy, 4' butoxytetrahydropyran-4-yloxy, 4 isobutoxytetrahydropyran-4-yloxy, 4'-amyloxytetrahydropyran-4'-yloxy, and 4'-hexoxytetrahydropyran-4'-yloxy of Za-methyI-Su, 19-norandrost-17,3-ol-3-one, 2a-methyl-5a-androst-175-01- 3-one, 4u-methyl-5oz,l9-norandrost-17fi-o1-3-one, and 4amethyl 5oz androst-l7B-ol-3-one, for example, are ob tained.

EXAMPLE 3 Repeating the procedure of Example 1 in every detail but one, namely, replacing 5a,19-norandrost-17-ol-3-one with androst-4- en-l7f3-ol-3-one, l7a-methylandrost-4-en-17fi-ol-3-one, 17a-ethylandrost-4-en-17/3-0l-3-one, l7a-propylandrost-4-en-l7B-ol-3-one, 7u-methylandrost-4-en-17B-ol-3-one, 4-chloroandrost-4-en-l7fi-ol-3-one, l9-norandrost-4-en-17-ol-3-one, l7a-methyl-l9-norandrost-4-en-17-ol-3-one, 17a-ethyl-19-norandrost-4-en-l7-o1-3-one,

13 6a methyl 17,8-(4'-methoxytetrahydropyran-4-yloxy)- 19-norandrosta4,6-dien-3,B-ol, and the like.

EXAMPLE 8 A mixture of 1 g. of 17(3-(4-methoxytetrahydro-pyran- 4'-yloxy)-19-norandrost-4-en-35-01, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, Washed with water, and dried to yield 3l3-acetoxy- 17B (4' methoxytetrahydropyran 4 yloxy) 19 norandrost-4-ene Which may be further purified through recrystallization from acetone:hexane.

Similarly, repeating this procedure with other products of Example 7 yields the corresponding 3 ,B-acetoxy derivatives, e.g., 3p3-acetoxy-17a,18-dimethyl-17,B-(4 methoxytetrahydropyran 4' yloxy) 19 norandrost 4 ene, 35 acetoxy 17oz methyl 17B (4' methoxytetrahydropyran 4' yloxy)androst 4 ene, 35 acetoxy 17aethyl 17B (4' methoxytetrahydropyran 4' yloxy)- 18-methylandrost-4-ene, and the like.

EXAMPLE 9 Repeating the procedure of Example 7 but replacing 17,3 (4 methoxytetrahydropyran 4' yloxy) 19 norandrost 4 en 3 one with 19 norandrost 4 en 175 o1 3 one19 norandrost 4 ene 3,8,17/3 diol is obtained.

A mixture of 1 g. of l9-norandrost-4-ene-3B,175-diol, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water, and the solid which forms is collected by filtration, washed with water, and dried. The mixture is chromatographed on neutral alumina, eluting with etherzhexane, to yield 17B-acetoxy-19-norandrost- 4-en-3fl-ol.

Repeating this sequence of procedures with other 19- norandrost 4 en 17,8 o1 3 ones, androst 4 en 17,8 o1 3 ones, 19 norandrostra 4,6 dien 17/3 o1 3 ones, and androsta 4,6 dien 17,8 o1 3 ones having hydrogen, methyl, chloro, or fluoro groups at C-6a and/or C-6fl (at C-6 with 4,6-dienes); hydrogen and lower alkyl groups at C-l7a; and hydrogen or methyl groups at (1-18 yields the corresponding 3/i-hydroxy-17aester compounds, e.g.,

17/3-acetoxy- 1 8-methylandro st-4-en-3 {3-01,

17 a, 1 S-dimethyl- 17p-acetoxyandrost-4-en-3 [3-01, 17ot-ethyl-17/3-acet0xy-18-methylandrost-4-en-3[3-01, 170t-methyl- 17 fi-acetoxyandrost-4-en-3 ,B-ol, 17a-ethyl-17B-acetoxyandrost-4-en-318-01, l7l3-acetoxyandrost-4-en-313-01,

17fl-acetoxy-1 8-methylandrosta-4,6-dien-3 [3-01, 17a,1S-dimcthyl-17p-acetoxyandrosta-4,6-dien-3;8-ol, 17a-ethyl l 7fi-acetoxyl 8-methylandrosta-4,6-dien-3B-ol, 17a-methyll 7fi-acetoxyandrosta-4,6-dien-35-01, 17a-ethyl-175-acetoxyandrosta-4,6-dien-3/3-ol, 17B-acetoxyandrosta-4,6-dien-3 5-01, and the like.

EXAMPLE l Repeating the procedure of Example 1 but replacing a,19-norandrost-17B-ol-3-one with 17,8-acetoxy-19-norandrost 4 en 3B ol3[3 (4 methoxytetrahydropyran 4 yloxy) 17;? acetoxy 19 norandrost 4 ene is obtained. Similarly, substituting the other products of Example 9 in this procedure yields the corresponding 3,8-ethers, e.g.,

3 [i- (4'-methoxytetrahydropyran-4'-yloxy) 17 B-acetoxyl8-methylandrost-4-ene,

3 ,8- (4'-methoxytetrahydropyran-4-yloxy) -1 70a, 1 8- dimethyl- 17fi-acetoxyandrost-4-ene,

3 5- 4-methoxytetrahydropyran-4-yloxy l 7a-ethyll 76- acetoxy- 1 8-methylandrost-4-ene,

313-(4'-methoxytetrahydropyran-4'-yloxy)-17a-rnethyl- 17 B-acetoxyandrost-4-ene,

313'- (4-methoxytetrahydropyran-4-yloxy) 1 7a-ethy1- 17ftacetoxyandrost-4-ene,

3 B- (4'-methoxytetrahydropyran-4-yloxy) 1713- acetoxyandrost-4-ene,

3/3-(4'-methoxytetrahydropyran-4'-yloxy) -17B-acetoxy- 18-rnethylandrosta-4,6-diene,

3/3-(4'-methoxytetrahydropyran-4'-yloxy)-l7u,18-

dimethyll 7/3-acetoxyandrosta-4,6-diene,

3 ,8- (4-methoxytetrahydropyran-4-yloxy) 17a-ethy1- 17fl-acetoxy-l 8-methylandrosta-4,6-diene,

3 fl- (4-methoxytetrahydropyran-4'-y1oxy) l7u-methyl- 17p-acetoxyandnosta-4,6-diene,

3p- (4-methoxytetrahydropyran-4-yloxy) -17a-ethyl- 17 fl-acetoxyandrosta-4,6-diene,

3 ,6- (4-methoxytetrahydropyran-4'-yloxy) 17B- acetoxyandrosta-4,6-diene,

3 B- (4'-methoxytetrahydropyran-4'-yloxy -l7[3- acetoxy-l 8-methyl-19-norandrost-4-ene,

3,8-(4-methoxytetrahydropyran-4-yloxy) -17a, 18-

dimethyl-17B-acetoxy-19-norandrost-4-ene,

3 p- (4-methoxytetrahydropyran-4'-yloxy) -17a-ethyll7B-acetoxy-l S-methyl-19-norandrost-4-ene,

3 [3- 4-methoxytetrahydropyran-4-yloxy -17a-methyl- 17fl-acetoxy-19-norandrost-4-ene,

3 ,8- 4'-methoxytetrahydropyran-4'-yloxy) l7a-ethy1- 17,8-acetoxy-19-norandrost-4-ene,

3,8- (4-methoxytetrahydropyran-4-yloxy) -17B-acet0xyl9-norandrost-4-ene,

3 ,B- (4-methoxytetrahydropyran-4-yloxy) -17B-acetoxy- 18-methyll 9-norandrosta-4, 6-diene,

3B-(4'-methoxytetrahydropyran-4-yloxy)-l7a,18-dimethyl-17fi-acetoxy-19-norandrosta-4,6-diene,

3 ,6- 4'-methoxytetrahydropyran-4'-yloxy) l7a-ethyl- 17B-acetoxy-l 8methyll9-norandrosta-4,6-diene,

3p- (4-methoxytetrahydropyran-4'-yloxy) -17a-methyll7B-acetoxyl9-norandrosta-4,6-diene,

3 ,8- 4'-methoxytetrahydropyran-4'-yloxy l7a-ethyl- 17 B-acetoxyl9-norandrosta-4,6-diene,

3fl-(4-methoxytetrahydropyran-4'-yloxy)-17,8-acetoxyl9-norandrosta-4,6-diene, and the like.

EXAMPLE 1 1 A solution of 1 g. of 3B-(4-methoxytetrahydropyran- 4 yloxy)-17a-methyl-17fi-acetoxy-19-norandrost-4-ene in 50 ml. of methanol is heated at reflux for three hours with a solution of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice Water and the solid which forms is collected by filtration, washed with water to neutrality, and dried to yield 33- (4' methoxytetrahydropyran 4 yolxy)-17ot-methyl 19-norandrost-4-en-175-01 which is recrystallized from methylene chloridezether.

Similarly, the other 17fl-ester products of Example 10 are converted to the corresponding 17,8-ols by this procedure.

EXAMPLE 12 Repeating the procedure of Example 7 but replacing 17a-ethylnyl 17,8 (4' methoxytetrahydropyran-4 yloxy) 19 norandrost-4en-3-one with Nix-methyl- 19-norandrost 4 en 17B-ol-3-one17a-methyl-19- norandrost-4-ene-3/3,l7 3-diol is obtained. Then repeating the procedure of Example 1 but replacing 5a,19-norandrost-17B-ol-3-one with 17 xmethyl l9 norandrost- 4-en-3fi,17B-diol and using 4 ml. instead of 2 ml. of 4'-methoxy-5,6'-dihydro 2H pyran-3B,17[3-bis(4'- methoxytetrahydropyran 4 yloxy) 17a methyl-19- norandrost-4-ene is obtained.

Repeating this sequence of procedures with other 19- norandrost-4-en-17fi-ol-3-ones, androst 4 en -01- 3-ones, 19-norandrosta 4,6 dien-l7fi-ol-3-ones, and androsta-4,6-dien-17fi-o1-3-ones having hydrogen, methyl, chloro, or fluoro groups at C-6u and/or C6,8 positions (at C6 with 4,6-dienes); hydrogen and lower alkyl groups at C-7a; and hydrogen or methyl at C18 yields i 15 the corresponding 3,3,17B-bisethers, e.g., 3/3,17,B-bis(4- methoxytetrahydropyran 4 yloxy)-17a-methylandrost- 4-ene, 313,175 bis(4-methoxytetrahydropyran-4-yloxy)- 17a,1S-dimethyl-l9-norandrost-4-ene, and the like.

EXAMPLE 13 Repeating the procedure of Example 1 but replacing 5a,l9-norandrost 175 ol-3-one with 19-norandrosta- 4,9(10)-dien 17B ol-3-one-17B-(4-methoxytetrahydropyran 4' yloxy)-19-norandr0sta-4,9(10)-dien-3- one is obtained.

Similarly, repeating this procedure with other 19- norandrosta-4,9(l)-dien 17/8 ol-3-ones and l9-norandrosta 4,9(10),11 trien-17/3-ol-3-ones having hydrogen and lower alkyl groups at C-17oc yields the corresponding 17p-(4-methoxytetrahydropyran 4 yloxy) compounds, e.g.,

17a-propyl-17/3-(4-methoxytetrahydropyran-4'-yloxy) 18-methyl-19-norandrosta-4,9(10)-dien-3-one,

175- (4'-methoxytetrahydropyran-4-yloxy -19-norandrosta-4,9(10)-dien-3-one,

17 5- (4-methoxytetrahydropyran-4'-yloxy) -18-methyl- 19-norandrosta-4,9 -dien-3-one,

17u-methyl-17fl- (4'-methoxytetrahydropyran-4'-yloxy)- l9norandrosta-4,9 10 -dien-3-one,

17a,1S-dimethyl-17/3-(4'-methoxytetrahydropyran-4'- yloxy) -19-norandrosta-4,9 10 -dien-3-one,

17a-ethyl-17/3- (4-methoxytetrahydropyran-4'-yloxy) 19-norandrosta-4,9(10)-dien-3-one,

17a-ethyl-17B-(4'-methoxytetrahydropyran-4'-yloxy) 18-methyl-19-norandrosta-4,9(10)-dien-3-one,

17;?-(4'-methoxytetrahydropyran-4'-yloxy) -18-methyl- 19-norandr0sta-4,9 10) ,1 1-trien-3-one,

17 18- (4-methoxytetrahydropyran-4-yloxy) -19-n0randrosta-4,9(10) ,1 1-trien-3-one,

17a-methyl-17fi- (4'-methoxytetrahydropyran-4-yloxy 19-norandrosta-4,9(10),11-trien-3-one,

17a,18-dimethyl-l7fi-(4'-methoxytetrahydropyran-4'- yloxy)-19-norandrosta-4,9(10),11-triene-3-one,

l7a-ethyl-l7 3- (4-methoxytetrahydropyran-4'-yloxy) 18-methyl-19-norandrosta-4,9(10),11-trien-3-one,

17a-ethyl-l7fi- (4-methoxytetrahydropyran-4-yloxy 19-norandrosta-4,9(10),11-trien-3-one,

17a-propyl-17fl- (4-methoxytetrahydropyran-4'- yloxy) -18-methyl-19-norandrosta-4,9 10) ,1 l-trien- 3-one,

17a-propy1-17/3-(4'-methoxytetrahydropyran-4'-yloxy) 19-norandrosta-4,9(10),11-trien-3-one, and the like.

EXAMPLE 14 A solution of 1 g. of 17,8-(4'methoxytetrahydropyran- 4' yloxy) 19 norandrosta 4,9(10) dien 3 one in 50 ml. of tetrahydrofuran is added over a 30-minute period to a stirred suspension of 1 g. of lithium tri-t-butoxy aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for two hours. To the mixture are cautiously added 5 ml. of ethylacetate and 2 ml. of water. Sodium sulfate is next added, the mixture is filtered, and the solid thus collected is washed with hot ethylacetate. The combined organic solutions are then evaporated to yield 17,8 (4' methoxytetrahydropyran- 4'-yloxy) 19 norandrosta 4,9(10) dien-3fi-ol which may be further purified through recrystallization from acetonezhexane.

Similarly, repeating this procedure with other products of Example 13 yields the corresponding 3fi-hydroxy de- [rivatives, e.g.

17a-propyl-17 3-(4-methoxytetrahydropyran-4'-yloxy)- 18-metyl-19-norandrosta-4,9 10) -dien-3B-ol,

17 18- (4'-methoxytetrahydro pyran-4'-yloxy) 19-norandrosta-4,9 1 0 -dien-3 {3-01,

1713-(4-methoxytetrahydropyran-4-yloxy) l 8-methyl- 19-norandrosta-4,9 (10)-dien-313-ol,

17a-methyl-17f3- (4'-methoxytetrahydropyran-4'-yloxy) 19-norandrosta-4,9 10) -dien-3 B-ol,

17a,18-dimethyl-17B-(4'-methoxytetrahydropyran-4'- yloxy)-19-norandrosta-4,9( 10) -dien-3fi-ol,

17a-ethy1- 17 3- 4-methoxytetrahydropyran-4-yloxy) 19-norandrosta-4,9 1O -dien-3p-o1,

17u-ethyl- 17 5- (4-methoxytetrahydropyran-4'-yloxy) 18-methyl- 19-norandrosta-4,9( 10 -dien-3 B-ol,

17p-(4'-methoxytetrahydropyran-4'-yloxy)-18-methyl- 19-norandrosta-4,9 10 ,1 1-trien-3 5-01,

- (4'-methoxytetrahydropyran-4-y1oxy) -19-norandrosta-4,9(l0),1l-trien-3fl-ol,

17a-methyl- 17 13- (4'-methoxytetrahydropyran-4'-yloxy) 19-norandrosta-4,9( 1O),11-trien-3;3-ol,

17u-18-dimethyl-17B-(4-methoxytetrahydropyran-4'- yloxy) l9-norandrosta-4,9 10),11-trien-3fl-ol,

17a-ethyl-17B-(4-methoxytetrahydropyran-4-yloxy) 18-methyl-19-norandrosta-4,9(10),11-trien-3,8-ol,

17u-ethyl- 17 fl- 4'-methoxytetrahydropyran-4'-yloxy 19-norandrosta-4,9(10),11-trien-3;8-ol,

17a-propy1-17/3-(4'-methoxytetrahydropyran-4'-yloxy)- 18-methyl-19-norandrosta-4,9=( 10 ,1 l-trien-BB-ol,

17a-propyl-17B- (4'-methoxytetrahydropyran-4-yloxy) 19-norandrosta-4,9 10) ,1 1-trien-3 18-01, and the like.

EXAMPLE 15 A mixture of 1 g. of 17,9-(4-methoxytetrahydropyran- 4-yloxy)-19-norandrosta 4,9(10),1l dien-3fl-ol, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water, and dried to yield 3 3 acetoxy-17fl-(4'-methoxytetrahydropyran 4'- yloxy)-l9-norandrosta-4,9(10)-diene which may be further purified through recrystallization from acetone:hex-

ane.

Similarly, repeating this procedure with other products of Example 14 yields the corresponding 3/3-acetoxy derivatives, e.g., 3B-acetoxy-17a, 18-dimethyl 17B (4'- methoxytctrahydropyran 4 yloxy) 19 norandrosta- 4,9(10)-diene, 35 acetoxy 17a ethyl 17,8 (4'-methoxytetrahydropyran 4' yloxy) 19 norandrosta 4,9 (10)-diene, 3/3 acetoxy 17a propyl 17 3 (4' methoxytetrahydropyran 4 yloxy) 18 methyl 19 norandrosta-4,9(10),1l-triene, and the like.

EXAMPLE 16 Repeating the procedure of Example 14 but replacing 17B (4 methoxytetrahydropyran 4' yloxy) l9- norandrost 4 en 3 one with 19-norandrosta-4,9(10)- dien 17p ol 3 one-19 norandrosta 4,9(10)- dime-3B, 17,8-diol is obtained.

A mixture of 1 g. of 19-norandrosta-4,9(10)-diene-3fl, 17/8-diol, 4 ml. of pyridine, and 2 ml. of acetic anyhdride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water, and the solid which forms is collected by filtration, washed with Water, and dried. The mixture is chromatographed on neutral alumina, eluting with etherzhexane, to yield 17fl-acetoxy- 19-norandrosta-4,9(10)-dien-3B-ol.

Repeating this sequence of procedures with other 19- norandrosta-4,5(10)-dien-17 3-ol-3-ones and 19-norandrosta 4,5 (10),11-trien-17/8-ol-3-ones having hydrogen and lower alkyl groups at 0-170: and hydrogen or methyl groups at C-18 yields the corresponding BB-hydroxy- 17u-ester compounds, e.g.,

17a-propyl-17p-acetoxy-18-methyl-19-norandrosta- 4,9(10)-dien-3/3-ol,

17fl-acetoxy-19-norandrosta-4,9 10) dien-3 18-01,

17/3-acetoxy-18-methyl-19-norandrosta-4,9( 10)-dien 17a-melthyl-1718-acetoxy-19-norandrosta-4,9 10) -dien- 17oz,18-dimethyl-17,8-acetoxy-19-norandrosta-4,9 10) dien-3 5-01,

17a-ethyl-17fl-acetoxy-19-norandrosta-4,9 -dien- 17a-ethyl-17fl-acetoxy-18-methy1-19-norandrosta-4,9

(10) -dien-3B-ol,

17B-acetoxy-18-methyl-19-norandrosta-4,9(10),11-trien- 17 fi-acetoxy- 19-norandro stat-4,9 10) 1 1-trien-3 {i-ol,

17a-methyl-17fi-acetoxy-19-norandrosta-4,9 10) ,1 1-

trien-3 5-01,

170:, 1 8-dimethyl- 17 fi-acetoxy- 1 9-norandrosta-4,9 10

11-trien-3,8-ol,

17ot-ethyll 7fl-acetoxyl 8-methyl- 1 9-norandro stat-4,9 10

11-trien-3 8-01,

17a-ethyl-17fl-acetoxy-19-norandrosta-4,9 10),11-

trien-3 3-01, and the like.

EXAMPLE 17 Repeating the procedure of Example 1 but replacing 50:,19 norandrost 176 -01 3 one with l7B-acetoxy- 19 norandrosta 4,9(10) dien 3,8 ol--3B (4- methoxytetrahydropyran 4 yloxy) 17,8 acetoxy-19- norandrosta 4,9(10) diene is obtained, Similarly, substituting the other products of Example 16 in this procedure, the corresponding 3fi-ethers are obtained, e.g.,

3fi- (4-methoxytethahydropyran-4'-yloxy) -17u-propyl- 17,8-acetoxy-1S-methyl-l9-norandrostra-4,9( 10 diene,

3fi-(4-methoxytetrahydropyran-4'-yloxy) -17,B-acetoxy- 19-norandrosta-4,9 10 -diene,

3 5- 4'-methoxytetrahydropyran-4'-yloxy l 7,8-acet0xy- 18-methyl-19-norandrosta-4,9(10)-diene,

3fi- (4-methoxytetrahydropyran-4-yloxy 17a-methyl- 17fl-acetoxyl 9-norandrosta-4,9( 10 -diene,

3 6-(4'-methoxytetrahydropyran-4-yloxy)-17a,18-dimethyl-17fl-acetoxy-19-norandrosta-4,9(10)-diene,

3,6-(4'-methoxytetrahydropyran-4'-yloxy)-17a-ethyl-17fiacetoxy-l 9-norandrosta-4,9( 10 -diene,

3,6-(4-methoxytetrahydroypran-4-yloxy) -17a-ethyl-17flacetoxy-1S-methyl-19-norandrosta-4,9(10)-diene,

3 B- 4'methoxytetrahydropyran-4-yloxy 17fl-acetoxy- 18-methyl-19-norandrosta-4,9(10),11-triene,

3fi-(4-methoxytetrahydropyran-4-yloxy) -17fl-acetoxy- 19-norandrosta-4,9(10),11-triene,

3B-(4'-methoxytetrahydropyran-4-yloxy) -17a-methyl- 17,8-acetoxy-19-norandrosta-4,9 10),11-triene,

3,8- (4'-methoxytetrahydropyran-4'-yl0xy -17a, 18-dimethyl-17B-acetoxy-19-norandrosta-4,9( l0),11- triene,

3/3-(4'-methoxytetrahydropyran-4-yloxy)-17a-ethyl-l 7(3- acetoxy-18-methyl-19-norandrosta-4,9(10),11- triene,

3B- (4--methoxytetrahydropyran-4-yloxy -1 7a-ethyl-17B- acetoxy-l9-norandrosta-4,9(10),1l-triene, and the like.

EXAMPLE 18 A solution of 1 g. of 3B-(4-methoxytetrahydropyran- 4-yloxy)-17a-ethyl-17,8-acetoxy 19 norandrosta 4,9 (10)-diene in 50 ml. of methanol is heated at reflux for three hours with a solution of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water to neutrality, and dried to yield 313- (4 methoxytetrahydropyant-yloxy)-17a ethyl 19- norandrosta-4,9(10)-dien-17fl-ol which is recrystallized from methylene chloridezether.

Similarly, the other 17B-ester products of Example 17 are converted to the corresponding 17fi-ols by this procedure, e.g., 3,8-(4' methoxytetrahydropyran-4'-yloxy)- 17 a-methyl-19-norandrosta-4,9 10) ,1 1-trien-17B-ol, etc.

EXAMPLE 19 Repeating the procedure of Example 14 but replacing 17,8-(4'-methoxytetrahydropyran-4'-yloxy) 19 noran- 18 drosta-4,9(10)-dien-3-one with 19-norandrosta 4,9(10)- dien-17B-ol-3-one-l9 norandrosta-4,9(10)-diene 3,8, 17fl-diol is obtained. Then repeating the procedure of Example 1 but replacing 5a,19-n0randrost-17/3-ol-3-one with 19-norandrosta-4,9(10)-diene-3fl,l7,8-diol and using 4- ml. instead of 2 ml. of 4-methoxy-56'-dihydro-2H- pyran3B,17B bis(4 methoxytetrahydropyran 4'- yloxy)-l9-norandrosta-4,9(10)-diene is obtained.

Repeating this sequence of procedures with other 19- norandrosta 4,9(10) dien-17B-ol-3-ones and 19-norandrosta-4,9 1 0) ,1 1-trien-17p-ol-3-ones having hydrogen and lower alkyl (e.g. methyl, ethyl) groups at C17oc and hydrogen or methyl at C18 yields the corresponding 3,8,175 bisethers, e.g., 36,l75-bis(4methoxytetrahydropyran-4-yloxy)- 17ot-methylandrosta-4,9(10)-diene, 3,8,176- bis(4-methoxytetrahydropyran 4 yloxy)-17a,18-dimethyl-l9-norandrosta-4,9(10),1l-triene, and the like.

The invention claimed is:

1. A 4' (lower)alkoxytetrahydropyran 4' yl steroid ether selected from the group consisting of (a) a member selected from the group consisting of (4' loweralkoxytetrahydropyran-4-yloxy)-5mandrostan 3 ones and 17p-(4'-loweralkoxytetrahydropyran 4-yloxy)-5ot,19-norandrostan-3-ones having at positions C2a and C4a, members selected from the group consisting of hydrogen and methyl, and at position C-l7oc, members selected from the group consisting of hydrogen and lower alkyl;

(b) a member selected from the group consisting of 17p (4' loweralkoxytetrahydropyranl'-yloXy)androst 4 en-3-ones and 17 ,8-(4'-loweralkoxytetrahydropyran 4 yloxy)-19-norandrost-4-en-3-ones having at position C-4a, a member selected from the group consisting of hydrogen and chloro; at position C-7a, a member selected from the group consisting of hydrogen, methyl, fluoro, and chloro; and at position C-17a, a member selected from the group consisting of hydrogen and lower alkyl;

(0) a member selected from the group consisting of 17,8 (4 loweralkoxytetrahydropyran-4'-yloxy)androsta 3,5 dienes and 176-(4 loweralkoxytetrahydropyran-4'-yloxy)-19-norandrosta-3,S-dienes having at position C-3, a member selected from the group consisting of lower alkoxy and lower cycloalkoxy; at position 'Cl7oc, a member selected from the group consisting of lower alkoxy and lower cycloalkoxy; at position C-17u, a member selected from the group consisting of hydrogen and lower alkyl; and at 0-18, a member selected from the group consisting of hydrogen and methyl;

(d) a 17,8 (4 loweralkoxytetrahydropyran-4-yloxy)- 5a-androst-1-en-3-one having at positions C-1 and C-2, members selected from the group consisting of hydrogen and methyl, at least one of said members at C1 and C-2 being methyl; and at position C-l7oc, a member selected from the group consisting of hydrogen and lower alkyl;

(e) a member selected from the group consisting of androst-4-enes and 19-norandrost-4-enes having at position C-3, a member selected from the group consisting of keto, hydrogen, hydroxy, conventional hydrolyzable esters of said hydroxy and 4-(lower) alkoxytetrahydropyran 4 yloxy; between positions C-6 and C7, a bond selected from the group consisting of single and double bonds; at position C6, first and second members selected from the group consisting of hydrogen, methyl, fluoro, and chloro, said second member being present only when the bond between 'C-6 and C7 carbons is a single bond; at position C17a, a member selected from the group consisting of hydrogen and lower alkyl; at position C-17B, a member selected from the group consisting of hydroxy, conventional hydrolyzable esters of said hydroxy, and 4 (lower)alkoxytetrahydropyran 4'- yloxy and at least one of said C-3 and C-17/3 posi- 19 tions having said 4-(lower)alkoxytetrahydropyran- 4'-y1oxy group; and at position C-18, a member selected from the group consisting of hydrogen and methyl;

(f) a 18-norandrosta-4,9(10)-diene having at position C3, a member selected from the group consisting of keto, hydrogen, hydroxy, conventional hydrolyzable esters of said hydroxy, and 4'-(lower)alkoxytetrahydropyran-4'-yloxy; between carbons at C-11 and C12, a member selected from the group consisting of single and double bonds; at position C17cz, a member selected from the group consisting of hydrogen and lower alkyl; at position C-17 8, a member selected from the group consisting of hydroxy, conventional hydrolyzable esters of said hydroxy, and 4' (lower)alkoxytetrahydropyran 4-yloxy and at least one of said C-3 and C-17fl positions having said 4' (lower)alkoxytetrahydropyran 4'-yloxy group; and at position C-18, a member selected from the group consisting of hydrogen and methyl.

2. The steroid ether of claim 1 wherein the ether is a member selected from the group consisting of 17fl-(4'- loweralkoxytetrahydropyran 4' yloxy)-a-androstan-3f ones and 17B (4'-loweralkoxytetrahydropyran-4'-yloxy)- 5a,19-norandrostan-3-ones having at positions C2oz and C4a, members selected from the group consisting of hydrogen and methyl, and at position C-17a, a member selected from the group consisting of hydrogen and lower alkyl.

3. The steroid ether of claim 2 wherein the ether is 20: methyl 17,3-(4'-methoxytetrahydropyran-4'-yloxy)- 5a-androstan-3-one.

4. The steroid ether of claim 2 wherein the ether is 40: methyl 17,8 (4-methoxytetrahydropyran-4-yloxy) 5a-androstan-3-one.

5. The steroid ether of claim 1 wherein the ether is a member selected from the group consisting of 17fl-(4- loweralkoxytetrahydropyran 4 yloxy)androst 4-en-3- ones and 1718-(loweralkoxytetrahydropyran-4'-yloxy)-19- norandrost-4-en-3-ones having at position 'C-4oz, a member selected from the group consisting of hydrogen or chloro; at position C-7a, a member selected from the group consisting of hydrogen, methyl, fluoro, and chloro;

and at position C-17a, a member selected from the group consisting of hydrogen and lower alkyl.

6. The steroid ether of claim 5 wherein the ether is 175 (4'-methoxytetrahydropyran-4'-yloxy)androst-4-en- 3-one.

7. The steroid ether of claim 5 wherein the ether is 4 chloro 17;3-(4-methoxytetrahydropyran-4'-yloxy)androst-4-en-3-one.

8. The steroid ether of claim 5 wherein the ether is 7a,l7oz dimethyl 17/9 (4-methoxytetrahydropyran-4'- yloxy)-19-norandrost-4-en-3-one.

9. The steroid ether of claim 5 wherein the ether is 17 3 (4-methoxytetrahydropyran 4' yloxy)-19-norandrost-4-en-3-one.

10. The steroid ether of claim 5 wherein the ether is 4 chloro-17B-(4-rnethoxytetrahydropyran-4'-yloxy)-19- norandrost-4-en-3-one.

11. The steroid ether of claim 5 wherein the ether is 7a-methyl-17,3-(4'-methoxytetrahydropyran 4 yloxy)- l9-norandrost-4-en-3-one.

12. The steroid ether of claim 1 wherein the ether is a member selected from the group consisting of 17/3-(4- loweralkoxytetrahydropyran 4 yloxy)androsta 3,5- dienes and 1713- (4'-loweralkoxytetrahydropyran-4-yloxy)- 19-norandrosta-3,5-dienes having at position C3, a member selected from the group consisting of lower alkoxy and lower cycloalkoxy; at position C-l7a, a member selected from the group consisting of hydrogen and lower alkyl; and at 0-18, a member selected from the group consisting of hydrogen and methyl.

13. The steroid ether of claim 12 wherein the ether is 20 3 cyclopentoxy 17a methyl 17p (4 methoxytetrahydropyran-4-yloxy) -19-norandrosta-3 ,S-diene.

14. The steroid ether of claim 12 wherein the ether is 3 cyclopentoxy :,18 dimethyl 17/3 (4 methoxytetrahydropyran-4-yloxy)-19-norandrosta-3,5-diene.

15. The steroid ether of claim 12 wherein the ether is 3 methoxy 17a,18 dimethyl 17B (4' methoxytetrahydropyran-4'-yloxy)-19-norandrosta-3,5-diene.

16. The steroid ether of claim 1 wherein the ether is a 1713 (4' loweralkoxytetrahydropyran 4 yloxy) 5aandrost-1-en-3-one having at positions C1 and C-2, members selected from the group consisting of hydrogen and methyl, at least one of said members at C1 and C2 being methyl and at position Cl7a, a member selected from the group consisting of hydrogen and lower alkyl.

17. The steroid ether of claim 16 wherein the ether is l methyl 1713 (4 methoxytetrahydropyran-4'-yloxy)- 5u-androst-1-en-3-one.

18. The steroid ether of claim 16 wherein the ether is 2 methyl 17,3 (4' methoxytetrahydropyran-4'-yloxy)- 5a-androst-l-en-3-one.

'19. The steroid ether of claim 16 wherein the ether is 2,170 dimethyl 17p (4' methoxytetrahydropyran 4'- yloxy)-5a-androst-1-en-3-one.

20. The steroid ether of claim 1 wherein the ether is selected from the group consisting of androst-4-enes and 19-norandrost-4-enes having at position C3, a member selected from the group consisting of keto, hydrogen, hydroxy, conventional hydrolyzable esters of said hydroxy and 4'-(lower)alkoXytetrahydropyran-4'-yloxy; between positions C6 and C7, a bond selected from the group consisting of single and double bonds; at position C6, first and second members selected from the group consisting of hydrogen, methyl, fiuoro, and chloro, said second member being present only when the bond between the C-6 and C-7 carbons is a single bond; at C-17a, a member selected from the group consisting of hydrogen and lower alkyl; at C-17fi, a member selected from the group consisting of hydroxy, conventional hydrolyzable esters of said hydroxy, and 4'-(lower)alkoxytetrahydropyran-4-yloxy and at least one of said C-3 and 0-173 positions having said 4'-(lower) alkoxytetrahydropyran-4'- yloxy group; and at position 0-18, a member selected from the group consisting of hydrogen and methyl groups.

21. The steroid ether of claim 20 wherein the ether is 17a-methyl 17,9 (4'-methoxytetrahydropyran-4'-yloxy)- l9-norandrost-4-en-3-one.

22. The steroid ether of claim 20 wherein the ether is 36 acetoxy 17oz methyl 17B (4' methoxytetrahydropyran-4-yloxy)-19-norandrost-4-ene.

23. The steroid ether of claim 20 wherein the ether is 170:,18 dimethyl 17 3 (4' methoxytetrahydropyran- 4-yloxy)-l9-norandrost-4-en-3-one.

24. The steroid ether of claim 20 wherein the ether is 3 acetoxy 170:,18 dimethyl 17 3 (4 methoxytetrahydropyran-4-yloxy)-19-n0randrost-4-ene.

25. The steroid ether of claim 20 wherein the ether is 60; fluoro 17a methyl 17B (4' methoxytetrahydropyran-4-yloxy)-19-norandrost-4-en-3-one.

26. The steroid ether of claim 20 wherein the ether is 60: fiuoro 1711,18 dimethyl 17,3 (4' methoxytetrahydropyran-4-yloxy)-19-norandrost-4-en-3-one.

27. The steroid ether of claim 20 wherein the ether is 6a,17a dimethyl 17B (4' methoxytetrahydropyran- 4-yloxy)-l9-norandrosta-4,6-dien-3-one.

28. The steroid ether of claim 20 wherein the ether is 611,18 dimethyl 17a ethyl 1713 (4' methoxytetrahydropyran-4'-yloxy)-19-norandrosta-4,6-dien-3-one.

29. The steroid ether of claim 20 wherein the ether is 3 (4 methoxytetrahydropyran 4' yloxy)- 19-norandrost-4-en-17,8-01.

30. The steroid ether of claim 20 wherein the ether is 3 (4 methoxytetrahydropyran 4 yloxy)-l7u-methyl- 17B-acet0xy-19-norandrost-4-ene.

31. The steroid ether of claim 20 wherein the ether is 21 3,175 bis(4 methoxytetrahydropyran 4 yloxy)-17amethyl-19-norandrost-4-ene.

32. The steroid ether of claim 1 wherein the ether is a l9-norandrosta-4,9(10)-diene having at position C3, a member selected from the group consisting of keto, hydrogen, hydroXy, conventional hydrolyzable esters of said hydroxy, and 4'-(lower)alkoXytetrahydropyran-4-yloxy; between carbons at C-11 and C-12, 21 member selected from the group consisting of single and double bonds; at position C-17u, a member selected from the group consisting of hydrogen and lower alkyl; at position C-17,8, a member selected from the group consisting of hydroxy, conventional hydrolyzable esters of said hydroxy, and 4- (lower)alkoxytetrahydropyran-4'-yloxy, and at least one of said C-3 and C-17fl positions having said 4-(lower) alkoxytetrahydropyran-4-yloxy group; and at position C- 18, a member selected from the group consisting of hydrogen and methyl.

33. The steroid ether of claim 32 wherein the ether is 36 (4' methoxytetrahydropyran 4 yloxy)-17a-ethy1- 19-norandrosta-4,9(10)-dien-17fi-ol.

34. The steroid ether of claim 32 wherein the ether is 22 17/3 (4 --methoxytetrahydropyran 4' yloxy) 19 norandrosta-4,9( 10) ,1 1-trien-3-one.

35. The steroid ether of claim 32 wherein the ether is 170: methyl 17B (4 methoxytetrahydropyran 4- yloxy)-19-norandrosta-4,9(10),11-trien-3-one.

36. The steroid ether of claim 32 wherein the ether is 36 (4 methoxytetrahydropyran-4'-yloxy)-17a-methyl- 19-norandrosta-4,9 10) ,1 1-trien-17 3-01.

References Cited UNITED STATES PATENTS 3,294,786 12/1966 Cross et a1 260-239.55 3,313,808 4/1967 De Ruggieri et a1. 260-239.55 3,326,903 6/1967 Klimstra 260239.55 3,338,925 8/1967 Fried 260-397.4 3,352,853 11/1967 Klimstra 260239.55

HENRY A. FRENCH, Primary Examiner U.S. CI. X.R. 

